Dendritic cells (DCs) are the most potent antigen (Ag)-presenting cells in the human body and have been employed in many tumor vaccine immunotherapy trials, sometimes with therapeutic impacts. DCs prepared from various sources display a wide range of characteristics in vitro and in vivo, and it remains uncertain as to which characteristics are most likely to promote successful immunotherapy.
In vitro, DC phenotypic maturation can be induced by a variety of agents, including CD40 ligand and toll-like receptor (TLR) agonists. The stimulatory effects of such agents, however, fall short of the DCs' potential to achieve DC1 polarization, the maximally effective state for promoting cell-mediated immunity.
The number of circulating DC precursors may be augmented by stem cell mobilizing treatments, notably granulocyte-macrophage colony-stimulating factor (GMCSF), granulocyte colony-stimulating factor (GCSF), Flt3 ligand (Flt3-L), and Flt3-L+GMCSF; however, the potential of such mobilized precursors to achieve DC1 polarization is unclear. For example, Flt3-L+GMCSF treatment induces abundant infiltration of DCs into mouse tumors, but such DCs retain an immature phenotype, activate regulatory T cells, and promote tumor growth. Because immunosuppressive factors such as IL-10, TGF-β, VEGF and PGE2 are often produced within the tumor milieu, such factors may prevent mobilized precursors from attaining maturation and DC1 polarization. Additionally, proliferative treatments themselves may negatively influence the later differentiation response of mobilized DC precursors.